Liver Toxicity Flashcards by Diana Bespalova

What is toxicity

Undesirable effect that may lead to cell death

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What is the difference between apoptosis and necrosis

Necrosis: unplanned cell death
Apoptosis: programmed cel death

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What are the key signs of apoptosis

Organelle swelling
ATP levels fall
Loss of plasma membrane integrity
Release of intracellular contents and digestion by lysosomal enzymes
Local inflammation

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What are the key signs of apoptosis

Signal dependent
ATP levels remain high
No release of cell contents
Digestion by caspase enzymes = no inflammation

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What are examples of direct and indirect toxicity

Direct: heat, oxygen deprivation and chemical damage
Indirect: pro-toxin that requires activation

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Why is the liver subjected to the toxic action of many xenobiotics?

Liver is the first organ to see xenobiotics after gut absorption
Liver expresses high levels of enzymes to metabolise xenobiotics

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What region of the liver activates paracetamol, CCl4, bromobenzene and allyl alcohol

Paracetamol, CCl4, bromobenze: centrilobular
Allyl alcohol: periportal

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Describe paracetamol metabolism at therapeutic doses

Phase 2 metabolism: 50/50 glucurondiation and sulfation

Small proportion via CYP3A4

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How does CYP3A4 metabolise paracetamol

N-hydroxylation
Loses H20 and rearrangement to NAPQI

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Describe paracetamol metabolism at supratherapeutic doses

Pathways oversaturated so higher proportion of paracetamol metabolised to NAPQI

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Describe the structure of the liver

Biggest internal organ
2 major lobes
2 sets of incoming blood hepatic and portal
Major blood supply is portal

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What are the 2 distinctive vessel structures in the liver

Central vein
Portal tract

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What other vessel structures are in the liver

Bile duct
Portal venue = from gut
Portal arteriole = branch of artery

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What are the 2 conceptual units of the liver

Lobule
Acini

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Describe the structure of a lobule

Make up lobes
Hexagonal in shape
Rows of hepatocytes that radiate from a central point

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Describe how hepatocytes are laid out in a lobule

Close contact with sinusoids
Adjacent to canaliculi

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How are arteries and veins layed out in hepatocytes

Branches of hepatic artery, portal vein and bile duct around perimeter
Cluster at corners of lobule forming portal triad
Central vein at mid-point of lobule

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Describe the blood flow in a lobule

Out of the sinusoids into central vein and transported out of liver

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Describe the expression of CYP2E1 in the lobule

Mainly around central veins and portal vein
More intense brown staining in those areas

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Describe the structure of the acini

Irregular shaped mass of hepatocytes
Small portal tract at the centre
Terminal hepatic venules at periphery

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Describe how the zones are layed out in the acini

1: surrounds portal tract (peri portal)
2: mid
3: surrounds hepatic venule (pericentral)

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Describe the blood flow in the acinus

Portal tract through the zones to the venule
Zone 1 (high O2) -> Zone 3 (low O2)

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What is the function of hepatocytes

Most functions of the liver
High metabolic activity

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Describe the function of Kupffer cells

Sit in sinusoid and allow blood to flow
Resident liver macrophages

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Describe the function of endothelial cells

Fenestrated - have holes in them to allow things to flow through Surround Kupffer cells

Describe the function of hepatic Stella te cells

Sit between hepatocytes and endothelial cells Store vitamin A Produce myofibroblasts in injury

Describe carbohydrate metabolism in the liver in the fed state

Glucose -> glycogen Glucose -> pyruvate -> Ac-CoA -> fatty acids, TGs Not much glycogen -> glucose Not much pyruvate -> lactate

Describe carbohydrate metabolism in the liver in the starvation state

Glycogen -> glucose Amino acids -> pyruvate -> glucose Main function is to reform glucose for survival

Describe carbohydrate metabolism in the liver in the CORI cycle

Muscle: Glucose -> pyruvate (produces small amount of ATP) Pyruvate -> lactate Liver: lactate -> pyruvate -> glucose Glycogen -> glucose Gluconeogenesis

What is the role of the liver in protein metabolism

Non-essential amino acid synthesis Amino acid re-amination Expression of serum transport proteins Clotting factors

How does the liver get rid of excess ammonia

Convert it to urea

What is the role of the liver in lipid metabolism

Fatty acid synthesis Triglyceride synthesis Cholesterol synthesis Bile acid synthesis Lipid oxidation

Describe the breakdown of erythrocytes

Spleen: RBC -> haem -> bilirubin Liver: glucuronidates bilirubin and excretes into bile

What causes jaundice

Build up of bilirubin in blood Suggests liver damage/failure

What is the function of Kupffer cells

Phagocytosis of particulates/bacteria Prevent contents of GI becoming systemic

Describe liver failure

Hepatocytes are damaged Localised to lobular region or acini

What biochemical markers are used as evidence of current damage

ALT AST Y-GT ALP

What biochemical markers are used as evidence of liver function

Bilirubin Ammonia and urea Pro-thrombin time

When would a liver biopsy be performed

When there is grade chronic liver damage

What are the pros and cons of a liver biopsy

+ : see liver structure and help diagnose causesof disease - : only see a fraction of liver and risks associated w procedure

What are the different stages of liver damage

1: steatosis 2: necrosis 3: fibrosis 4: cirrhosis 5: primary liver cell cancer

How does GSH protect cells

GSH nucleophillic 2e- in thiol group attract electrophillic sulfhydryl reactive agents and conjugates with them Reduce oxidised thiols

When does toxicity to paracetamol occur

When GSH is depleted by NAPQI by 80%

What are the antidotes to paracetamol toxicity

N acetyl cysteine or methionine

Why is methionine not as routinely used in paracetamol overdose

Affects folic acid levels Long term effect on the heart

How can GSH reduce H2O2

GSH peroxidase acts on H2O2 and converts it to H20 GSH reductase converts oxidised GSH to GSH

Why is GSH reductase important

Oxidised GSH (GSSG) can’t protect thiols Need to be reduced back to GSH

Whats a better animal model of paracetamol toxicity

Mouse not rat Rat have a greater basal and active capacity for hepatic stress response

Describe CCl4

Toxin that produces cell death in hepatocytes

Describe the activation hypothesis of CCl4

Reduced by CYP450 (addition of e-) = homolytic fission of covalent bond = chloride ion + trichloromethyl radical

In what area is necrosis due to CCl4 seen in

Centrilobular region Activated by CYP2E1

What are the biochemical effects of CCl4 intoxication on the ER

ER degranulation and swelling within2 hours ER enzyme inactivation

Is CCL4 mutagenic

Not mutagenic Weak carcinogen

What is the biochemical effects of CCl4 intoxication on the mitochondria

Intact for several hours then swell Uncontrolled respiration Depleted ATP Inactivated enzymes

Describe how CCl4 forms a peroxytrimethyl radical

CYP450s reduce CCl4 = trimethyl radical (CCl3) CCl3 + O2 dissolved in membrane = peroxytrimethyl radical (CCl3O2)

What happens after CCl3O2 is formed from CCL4

Radical extracts H+ and e- from lipid to from lipid radical Lipid radical reacts w O2 = peroxylipid radical (LOO) LOO + another lipid = lipid hydroperoxide and new lipid radical Affects membrane fluidity as more radicals will form as long as O2 is present

What can prevent lipid peroxidation and what is the mechanism

Vitamin E Inhibits process to a some extent by reacting with radicals to from stable radical

What is an allyl alcohol

3 carbon molecule that has an alcohol

Describe the metabolism of allyl alcohols

Alcohol ——————> aldehyde ————————> acid Alcohol dehydrogenase Acetaldehyde dehydrogenase

How does the body prevent aldehyde toxicity

ALDH is very fast to keep low levels of aldehydes

How are aldehydes reactive

O=C-H is reactive to amines and thiols e.g proteins and biogenic amines Depleted GSH from cells